It is commonly accepted that once a therapeutic agent such as a drug or cell is administered to a subject, the biodistribution, therapeutic and side effects are largely dependent on how the agent interacts with different tissues. Although much work has gone into developing the magic bullet using targeting ligands or other technologies to bind agents to their intended targets, much less work has been done to make the targets easier to hit. In this proposal, we will be focusing on using image guided pulsed high intensity focused ultrasound (pHIFU) to increase permeability of tissues to therapeutic agents. The technique employed here, unlike other competing techniques, does not use ultrasound contrast agents or explicitly rely on cavitation. The actual mechanism is, in fact unclear. Nevertheless, our preliminary studies demonstrated that pHIFU treatment in animal models, without the use of microbubble contrast agents, consistently improves local delivery of macro-molecular agents and has also been associated with improved therapeutic outcomes. We have also demonstrated that pHIFU can facilitate thrombolysis. The major hurdle to be overcome at this point is to demonstrate that the method will safely and effectively translate from the murine muscle and tumor models to larger animal geometries. This is the first goal of the proposed research. The second goal is to further elucidate the mechanism behind the effect to develop a strategy for optimization of the procedure for clinical use. To be successful, we will need to achieve the following specific aims in the 5 yrs of the proposed project: 1. Modify the InSightec MR guided HIFU system for drug delivery based on our preliminary mouse work. 2. Explore the pulsed-HIFU parameter space with a broad range of measurement tools to find optimum efficacy and safety in rabbit muscle. 3. Develop a working theoretical model of the pulsed-HIFU - tissue interaction based on data generated in Aim 2. 4. Demonstrate optimum delivery in rabbit V2 carcinoma model based on techniques and principles developed in Aims 2 and 3. 5. Demonstrate our ability to increase the delivery of the monoclonal antibody LM609 to V2 carcinoma to therapeutically relevant levels. Public Health Relevance Statement (provided by applicant): In this proposal we will be focusing on using image guided pulsed high intensity focused ultrasound (pulsed-HIFU) to increase permeability of tissues to therapeutic agents focally to facilitate therapeutic agent localization. The long term goal is to use the combination of image guided physical energy deposition with smart design of chemical and biologic therapeutic agents to provide spatial and temporal control of delivery, activation and selectivity of therapeutic agents. This should allow us to have therapeutic agents that we can send to the right place at the right time and have the desired effects on the right cells.